Imatinib (N-{5-[4-(4-methyl-piperazinomethyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine) is represented by the following structural formula (I):

Imatinib is known as an inhibitor of tyrosine kinases and is indicated for the treatment of chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors.
Imatinib is sold in the U.S. by Novartis as Gleevec™ capsules containing imatinib mesylate equivalent to 100 or 400 mg of imatinib free base.
U.S. Pat. No. 5,521,184 and WO 03/066613 describe synthetic routes for preparing imatinib. One synthetic process, depicted in Scheme 1, involves reacting 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester with 3-nitro-4-methyl-aniline to obtain N-(4-methyl-3-nitrophenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reduced to obtain N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benizamide. The latter is reacted with cyanamide (NH2CN) in a mixture of concentrated hydrochloric acid solution and n-butanol to produce N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reacted with 3-dimethylamino-1-pyridin-3-yl-propenone to obtain imatinib.

Another process, depicted in Scheme 2, involves reacting 3-bromo-4-methyl-aniline with 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester to obtain N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with 4-(3-pyridyl)-2-pyrimidine amine (which is obtained by reacting cyanamide with 3-dimethylamino-1-pyridin-3-yl-propenone) to obtain imatinib.

Yet another process, depicted in Scheme 3, includes obtaining 2-methyl-5-nitrophenyl-guanidine from 2-amino-4-nitro-toluene by adding nitric acid to a solution of the latter in ethanol followed by addition of cyanamide. The product is subsequently reacted with 3-dimethylamino-1-pyridin-3-yl-propenone to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, which is subsequently reduced and reacted with 4-(4-methyl-piperazinomethyl)-benzoyl chloride to obtain imatinib.

The syntheses described in U.S. Pat. No. 5,521,184 and WO 03/066613 are not particularly suitable for industrial purposes. For example, the reaction between N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide and 4-(3-pyridyl)-2-pyrimidine amine, which uses a reagent mixture of rac-BINAP (a phosphine oxide catalyst) and Pd2(dba)3*CHCl3 (Example 10 in WO 03/066613). These catalysts are very expensive and not suitable for commercial production.
WO 2004/074502 (hereinafter the '502 application) describes a coupling reaction between N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine and 4-(4-methyl-piperazin-1-ylmethyl)-benzoyl chloride, wherein DMF is used instead of pyridine. However, the method described in the '502 application lacks an advantage in that the coupling reaction produces the hydrohalide salt of imatinib, e.g., imatinib trihydrochloride monohydrate, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required. Further, conventional methods for coupling N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine require reaction with an acid halide, e.g., 4-(4-methyl-piperazin-1-ylmethyl)-benzoyl chloride, which requires an additional production step that can involve harsh and/or toxic chlorinating agents.
Thus, there is a need in the art for an imatinib production process that uses less hazardous, more environmentally friendly reagents and solvents, and uses fewer synthetic steps. The present invention provides such a process.